Short CommunicationVariable phenotype in 17q12 microdeletions: Clinical and molecular characterization of a new case
Introduction
Recurrent genomic rearrangements of chromosome 17q12 are associated with varied clinical phenotypes. In particular, microdeletions encompassing the hepatocyte nuclear factor 1beta gene (HNF1B, OMIM 189907) are considered the cause of Renal Cysts and Diabetes (RCAD) syndrome, an autosomal dominant disorder (Bingham et al., 2004). This condition results in a clinically distinguishable phenotype, whose major features include cystic renal disease, renal anomaly, maturity onset diabetes of the young type 5 (MODY5), pancreatic atrophy, and liver abnormalities (Bellanné-Chantelot, 2005, Nagamani et al., 2010).
Also, deletions in 17q12 have recently been identified as a rare cause of Mayer–Rokitansky–Küster–Hauser Syndrome (MRKH). This syndrome is defined in 46,XX women by congenital absence of the uterus and upper part of the vagina with otherwise normal sexual development and can be associated with renal, skeletal and/or hearing defects (Bernardini et al., 2009, Nik-Zainal et al., 2011 The 17q12 microdeletions are not characterized by intellectual disability or other neurobehavioral phenotypes, while it was observed that the duplication of the same region causes intellectual disability, autism spectrum disorder and speech delay (Brandt et al., 2012). Although earlier reports of cases with the 17q12 microdeletion syndrome did not include cognitive impairment as a part of the characteristic phenotype of these deletions (Mefford et al., 2007), recently, some authors (Dixit et al., 2012, Loirat et al., 2010, Mukamel et al., 2011) have reported rare cases with intellectual impairment, with or without autism, suggesting that cognitive impairment and a behavioral phenotype could be part of the clinical features conveyed by the 17q12 microdeletion. In order to deeply investigate the phenotype associated with 17q12 microdeletion, we describe the clinical and molecular data of a patient carrier of a de novo deletion in the 17q12 region, 1.42 Mb in size, with dysmorphic features, serious speech delay, intellectual disability (ID), stereotyped behaviors and obesity, but without the typical clinical features usually present in patients harboring this deletion. Finally, we discuss candidate genes for the observed traits and, in particular, we discuss the possible role of involvement of MIR2929 in the del17q12 neurological phenotype observed in our patient.
Section snippets
Clinical description
The patient is a 12-year-old boy whose parents are non-consanguineous. There is no family history of ID, autism, or other psychiatric illness. He was born at 41 weeks of gestation by cesarean section. The child had been naturally conceived and the parents were not aware of any abnormalities on prenatal ultrasounds. At birth an echocardiographic exam was performed, which showed transposition of great arteries, surgically treated at 40 days of life.
Developmental milestones were normal until 14
Snp array assay
Blood was obtained from the proband and his parents after signed informed consent. The study was designed to perform parental and proband samples concurrently on three individual chips. Genomic DNA was isolated from peripheral blood lymphocytes of the patient and the parents by using BioRobot EZ1 (Quiagen, Solna, Sweden). DNA concentration and purity were determined with a ND-1000 Spectrophotometer (NanoDrop Technologies, Berlin, Germany) while SNP-array analysis was performed by using
Results
SNP-array analysis of the proband revealed a heterozygous deletion involving interstitial chromosome 17q12, from SNP_A-8624766 (34,816,256 bp) to SNP_A-1828153 (36,244,358 bp; rs1963088) (USCS Genome Browser build February 2009 hg19), which were the first and the last deleted oligonucleotide from the centromere respectively. The flanking normal probes were CN_754222 (34,629,684 bp) and CN_763010 (36,282,179 bp). The subsequent microarray analysis of the proband's parents using the same platform
Discussion
The 17q12 deletion, involving HNFB1 gene, is associated with the RCAD (renal cysts and diabetes) syndrome, characterized by cystic renal disease, renal anomaly, MODY5, pancreatic atrophy and liver abnormalities. In some cases the same deletion is associated with MRHK (Mayer–Rokitansky–Küster–Hauser) syndrome, characterized by congenital absence of the uterus and upper part of vagina with otherwise normal sexual development in 46,XX women and can be associated with renal, skeletal and/or hearing
Conflict of interest
The authors declare that they have no competing interests.
Acknowledgments
This study was supported by a grant from the Italian Ministry of Health (Ricerca Corrente 2013) and by the “5x1000” voluntary contributions to MC. We would like to thank the patient and his family for their cooperation.
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2023, American Journal of Medical Genetics, Part A
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